Casey JD, Seitz KP, Driver BE, et al; RSI Investigators and the Pragmatic Critical Care Research Group. Ketamine or Etomidate for Tracheal Intubation of Critically Ill Adults.
Etomidate's adrenal suppression concern pushed a generation of clinicians toward ketamine as the "safer" induction agent for hemodynamically fragile patients. This trial tested whether that switch actually helps.
Peri-intubation cardiovascular instability is common and dangerous: the INTUBE study found it in 43.4% of critically ill intubations, with an adjusted OR of 2.47 for ICU mortality when it occurred. Etomidate causes transient adrenal suppression via 11-beta-hydroxylase inhibition, which pushed many clinicians toward ketamine as the reflexive "hemodynamically neutral" alternative for sick patients — a belief based largely on smaller trials and physiologic reasoning rather than a large, pragmatic head-to-head test in the sickest population.
| Design | Multicenter, pragmatic, randomized, open-label trial, intention-to-treat analysis |
| Population | 2,365 critically ill adults undergoing tracheal intubation in an ED or ICU at 14 US hospitals; excluded trauma, pregnancy, prisoners |
| Groups | 1,176 ketamine (1–2 mg/kg IV, actual body weight) vs. 1,189 etomidate (0.2–0.3 mg/kg IV, actual body weight) |
| Case mix | ~Half with sepsis/septic shock; ~20% already on vasopressors at time of intubation; average age ~60; >99% received their randomized drug |
| Primary outcome | In-hospital death by day 28 |
| Cardiovascular collapse defined as | SBP <65 mmHg, new or increased vasopressor dose, or cardiac arrest during intubation |
| Outcome | Ketamine | Etomidate | Result |
|---|---|---|---|
| In-hospital death by day 28 | 330/1,173 (28.1%) | 345/1,186 (29.1%) | Adjusted risk diff −0.8 pts (95% CI −4.5 to 2.9), P=.65 |
| Cardiovascular collapse during intubation | 260/1,176 (22.1%) | 202/1,189 (17.0%) | Risk diff +5.1 pts (95% CI 1.9 to 8.3) — more common with ketamine |
No mortality benefit for ketamine over etomidate — the drugs performed essentially identically on the outcome that mattered most. But ketamine produced more cardiovascular collapse, not less, driven mainly by new or increased vasopressor requirements rather than cardiac arrest itself. This directly inverts the assumption that drove many departments to switch away from etomidate in unstable patients.
Not "which drug is safer" — "prepare for instability regardless of which drug you pick."
The consistent message across independent commentary on this trial: the actual lesson isn't a verdict on ketamine vs. etomidate, it's that neither agent is a hemodynamic free pass in critically ill patients. Whichever induction agent is chosen, have vasopressors drawn up and ready, anticipate peri-intubation hypotension as the default expectation rather than the exception, and treat the induction-agent choice as one input among several (respiratory status, adrenal concerns, familiarity) rather than the primary lever for preventing collapse.
The source post's framing holds up precisely: "ketamine because it's hemodynamically neutral" is a belief this trial directly tests and doesn't support. No mortality difference between ketamine and etomidate, but significantly more cardiovascular collapse with ketamine (22.1% vs 17.0%), driven by vasopressor escalation. This is the largest, most pragmatic head-to-head trial on this question to date, and its message is preparation over drug selection: assume peri-intubation instability is coming, regardless of which agent you reach for.